Coughing provides a means for clearing the tracheal and bronchial trees of a accumulated secretions and/or foreign bodies. The mechanism of coughing is initiated by an appropriate stimulus which elicits a deep inspiration, followed by closure of the epiglottis and relaxation of the diaphragm. Thereafter, a sharp muscle contraction against the closed epiglottis occurs, thereby, producing increased pressure in the intra-thoracic and intra-airway passages. The positive intra-thoracic pressure causes a narrowing of the trachea due to enfolding of its compliant posterior membrane and opens the epiglottis. When the epiglottis opens, the combination of the large pressure differential between the thoracic cavity and the atmosphere, coupled with the narrowing of the trachea, produces a massively increased rate of air flow through the trachea. The force created by this increased rate of air flow can effect the clearance of expectorate mucus and foreign materials from the airway.
Coughing is caused by a variety of stimuli, including physiological, mechanical, or chemical stimuli. For example, coughing is produced by inflammatory mechanisms, mechanical disorders, and chemical and thermal stimulation. Also for example, inflammatory stimuli can be initiated by edema of the mucosal membranes. The edema, in turn, can be from any etiology, for example, bacterial or viral infection, the common cold, or excessive cigarette smoking. Inflammatory stimuli may also be elicited by irritation from exudative processes such as post-nasal drip and gastric reflux. Such stimuli may arise in the airways, for example as in laryngitis, bronchitis, pneumonia or an abscess in the lungs.
Further, mechanical stimuli, for example the inhalation of particulate matter, can cause coughing. Other mechanical disorders which result in compression of the air passages or increased pressure upon any area of the respiratory system may result in coughing. Such mechanical difficulties may arise from intra-mural or extra-mural etiologies. For example, extra-mural causes of coughing include extra-mural pressure caused by an aortic aneurysm, granulomas, pulmonary neoplasms, mediastinal tumors, and the like. Intra-mural lesions, such as bronchiogenic carcinoma, bronchial adenoma, the presence of foreign bodies or bronchial asthma also result in coughing. Decreased pliancy of the respiratory membranes may also result in chronic coughing, as in the case of patients suffering from cystic fibrosis.
Chemical stimuli, for example the inhalation of irritant gases (e.g., cigarette smoke or chemical fumes) may also elicit coughing. Other chemical entities result in coughing due to their reactive effect upon the respiratory system itself or on the balance and uptake of respiratory gases. Additionally, many chemical agents induce coughing due to their reaction with enzymes involved in the respiratory process. Lastly, thermal stimuli, such as the inhalation of either very hot or cold air, may also result in coughing.
In some disease states, a persistent cough can be the only or primary symptom. For example, patients suffering from bronchial asthma can result in incessant coughing. Moreover, in some medical conditions, for example, asthma, the cough mechanism itself may further aggravate the patient's condition. Asthma is a condition marked by recurrent attacks of paroxysmal dyspnea with wheezing, which is due to spasmodic contraction of the bronchi. The condition is caused by various etiologies. In some cases, asthma is the result of an allergic reaction. A variety of factors including vigorous exercise, chemical or particulate irritation, or even psychological stress can stimulate or provoke coughing. Moreover, the violent contractions of the thoracic cavity which accompany coughing further aggravates already irritated respiratory membranes. A review of the physiology of coughing is presented by Karlsson et al., Pulmonary Pharmacology and Therapeutics (1999) 12:215-238.
A variety of antitussive drugs have been developed for the treatment of coughing, for example, morphine-like compounds and compounds that act on opioid receptors. However, these compounds have adverse side effects. For example, the use of morphine-like compounds are known to result in addiction, respiratory suppression, and inhibitory action of smooth muscle contraction (e.g., resulting in constipation), and psychotomimetics. In particular, codeine is known to be highly addictive and dextromethorphan is known to induce hallucinations, delusions, or other symptoms of a psychosis. Moreover, drugs having strong antitussive activity, for example codeine and dextromethorphan, are known to adversely act on the central nervous system. Further, drugs that act on opioid receptors are known to adversely effect urination (Leander et al. Pharmacol. Exp. Ther., 227:35 (1983). A review of antitussive drugs is presented by Hey et al., Annual Reports in Medicinal Chemistry 35:53-62 (2000) and Bolser, Pulmonary Pharmacology 9:357-364 (1996).
A variety of drugs are available for the treatment of coughing. However, the number of safe and effective antitussive agents devoid of unwanted side effects, for example, sedation and addiction, is limited. In view of the serious adverse side effects of the drugs used to treat coughing, there is a need for antitussive drugs that are free of such side effects and are effective in reducing or suppressing coughing. The present invention fulfills these and other needs.